A role for surface hydrophobicity in protein-protein recognition

Authors

  • L. Young,

    1. Laboratory of Mathematical Biology, Division of Cancer Biology Diagnosis and Centers, National Cancer Institute, National Institutes of Health, Bethesda, Maryland 20892
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  • R.L. Jernigan,

    1. Laboratory of Mathematical Biology, Division of Cancer Biology Diagnosis and Centers, National Cancer Institute, National Institutes of Health, Bethesda, Maryland 20892
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  • D.G. Covell

    Corresponding author
    1. Biomedical Supercomputing Laboratory, PRI/Dyncorp, Frederick Cancer Research and Development Center, National Cancer Institute, Frederick, Maryland 21702
    • PRI/DynCorp, NCI — Frederick Cancer Research and Development Center, P.O. Box B, Frederick, Maryland 21702-1201
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Abstract

The role of hydrophobicity as a determinant of protein-protein interactions is examined. Surfaces of apo-protein targets comprising 9 classes of enzymes, 7 antibody fragments, hirudin, growth hormone, and retinol-binding protein, and their associated ligands with available X-ray structures for their complexed forms, are scanned to determine clusters of surface-accessible amino acids. Clusters of surface residues are ranked on the basis of the hydrophobicity of their constituent amino acids. The results indicate that the location of the co-crystallized ligand is commonly found to correspond with one of the strongest hydrophobic clusters on the surface of the target molecule. In 25 of 38 cases, the correspondence is exact, with the position of the most hydrophobic cluster coinciding with more than one-third of the surface buried by the bound ligand. The remaining 13 cases demonstrate this correspondence within the top 6 hydrophobic clusters. These results suggest that surface hydrophobicity can be used to identify regions of a protein's surface most likely to interact with a binding ligand. This fast and simple procedure may be useful for identifying small sets of well-defined loci for possible ligand attachment.

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